1. Field of the Invention
This invention relates to a method for purifying ibuprofen-comprising mixtures of the kind which are typically produced during a reaction process in which ibuprofen (2-(4'-isobutylphenyl)propionic acid) is formed.
2. Background Art
Ibuprofen is a well-known nonsteroidal anti-inflammatory drug which has been converted from ethical, i.e., prescription, to over-the-counter status. The ibuprofen sold as a pharmaceutical must meet purity requirements specified by the U.S. Food and Drug Administration. In addition, the ibuprofen is typically sold over-the-counter in the form of tablets, and therefore it is advantageous to have the ibuprofen material be in a structural form which can be readily formed into tablets; typically tablet formation is facilitated when the average crystal size of the ibuprofen material ranges from about 15 microns to about 70 microns.
Ibuprofen-comprising mixtures which can be processed by the method of the present invention to yield purified ibuprofen which is capable of meeting U.S. Food and Drug Administration requirements include those produced by the methods such as the method described in U.S. patent application Ser. No. 07/500,645, filed Mar. 28, 1990 U.S. Pat. No. 4,981,995. U.S. patent application Ser. No. 07/500,645 U.S. Pat. No. 4,981,995 is hereby incorporated by reference for purposes of providing background information helpful in understanding the present invention.
When ibuprofen is produced as described in U.S. patent application Ser. No. 07/500,645, U.S. Pat. No. 4,981,995 the process involves the carbonylation of 1-(4'-isobutylphenyl)ethanol (IBPE) with carbon monoxide while in contact with an acidic aqueous medium at a temperature of at least about 10.degree. C. and a carbon monoxide pressure of at least about 500 psig, and in the presence of (1) a catalyst consisting essentially of a palladium compound in which the palladium has a valence of zero to 2 and is complexed with at least one acid stable monodentate phosphine ligand freely miscible with the organic phase of the reaction medium, the phosphorus:palladium mole ratio in said palladium compound and ligand being at least about 2:1 when the mole ratio of palladium to IBPE is such that palladium=1 and IBPE=10,000 or more; (2) dissociated hydrogen ions from an acid which is substantially completely ionizable in a dilute aqueous solution, such that the mole ratio of hydrogen ions to IBPE added to the reaction zone (H /IBPE) is at least about 0.15; and (3) dissociated halide ions such that the mole ratio of halide ions to IBPE added to the reaction zone (X.sup.- /IBPE) is at least about 0.15.
The IBPE used to produce ibuprofen may be made by any of various means; preferably, however, the carbonylation reaction to produce ibuprofen is integrated with a method of producing IBPE from isobutylbenzene, wherein the latter compound is subjected to a Friedel-Crafts reaction with an acetylating agent to produce 4-isobutylacetophenone (IBAP) which is then reduced with hydrogen in the presence of a hydrogenation catalyst, or with a reducing agent containing available hydrogen, to obtain IBPE.
The crude reaction product mixture obtained in the above-described carbonylation reaction, contains ibuprofen at a concentration range of about 70% to about 98% by weight, and typically contains about 85%-95% by weight, having such undesirable impurities present as triphenylphosphine (TPP), triphenylphosphine oxide (TPPO), and organometallic compounds/complexes (typically organo-palladium compounds/complexes) which need to be removed.
Inorganic impurities typically present include hydrochloric acid, palladium-containing compounds and elemental palladium which also need to be removed.
Additional organic impurities, such as (but not limited to) 4-isobutylacetophenone, isobutylbenzene, 1-(4'isobutylethylbenzene, 1-(4'isobutylphenyl)ethyl chloride, 1-(4'-isobutylphenyl)ethanol, isopropylalcohol, isopropyl ester of ibuprofen, 3-(4'-isobutylphenyl)propionic acid and 2-(3'-isobutylphenyl)propionic acid are also typically present in the reaction product to be purified.
Several different methods of purification were initially attempted, including the most commonly used method of purification for similar reaction product materials, crystallization from a hydrocarbon solvent. However, it was discovered that such crystallization alone of the ibuprofen reaction product mixture was not sufficient to remove the TPP and TPPO. In fact, analytical data confirmed that very little if any TPP was removed by crystallization from hydrocarbon solvents.
In addition, crystallization from a hydrocarbon solvent did not remove metallic catalyst compounds/complexes from the reaction product mixture.
Melt crystallization and distillation of the ibuprofen reaction product mixture were also investigated as possible means of ibuprofen purification. Melt crystallization was investigated, but preliminary experiments indicated that due to the high viscosity of the crude ibuprofen and its individual constituents, melt crystallization is inefficient as an individual method of separation. For example, the TPP and TPPO combined concentration in the melt crystallized ibuprofen product was greater than the desired concentration of 10 ppm or less. Melt crystallization appears to be more expensive than distillation as a separation purification method. Although distillation appears to be a feasible method of purification, economic calculations show distillation, as an individual separation technique, to be expensive relative to crystallization from solvents; and, when distillation is used typically the 3-isomer is carried overhead with the ibuprofen (4-isomer), requiring subsequent processing for removal of the 3-isomer. The distillate ibuprofen product is in the form of oil which is typically cooled/solidified on a chilled drum and subsequently flaked. Conversion of the ibuprofen flakes to a particle size commonly used to manufacture tablets is difficult due to mechanical complexities.
Distillation, as a method of purifying an ibuprofen reaction product mixture, is disclosed in U.S. patent application Ser. No. 07/302,696, filed Jan. 25, 1989 now abandoned. This application disclosed a process for purifying 2-(4'-isobutylphenyl)propionic acid from a mixture, wherein the 2-(4'-isobutylphenyl)propionic acid is separated as a distillate fraction, by subjecting the mixture to a vacuum rectification.